4-(3-amino-2-substituted propoxy)indole derivatives

ABSTRACT

THIS INVENTION CONCERNS NOVEL COMPOUNDS OF THE FORMULA:   2-R2,3-R3,4-(R1-NH-CH2-CH(-OOC-R4)-CH2-O-)INDOLE   WHEREIN R1 IS ALKYL OF 1 TO 6 CARBON ATOMS, CYCLOALKYL OF 3 TO 6 CARBON ATOMS, PHENYLALKYL OF 8 TO 12 CARBON ATOMS WHEREIN THE PHENYL RADICAL IS SEPARATED FROM THE NITROGEN ATOM BY AT LEAST 2 CARBON ATOMS, 1,1-DIMETHYL2-PROPINYL OR ALLYL, R2 IS HYDROGEN, METHYL, CARBAMOYL, OR CARBAMOYL MONO- OR DISUBSTITUTED BY ALKYL OF 1 TO 4 CARBON ATOMS, R3 IS HYDROGEN OR METHYL, AND R4 IS ALKYL OF 1 TO 17 CARBON ATOMS, CYCLOALKYL OF 3 TO 7 CARBON ATOMS, CYCLOALKYL OF 3 TO 7 CARBON ATOMS SUBSTITUTED BY ONE OR MORE ALKYL SUBSTITUENTS OF 1 TO 4 CARBON ATOMS, PHENYL, PHENYL MONOSUBSTITUTED BY METHYL, METHOXY, FLUORINE OR CHLORINE, OR CHLOROALKYL OF 1 TO 7 CARBON ATOMS, AND ACID ADDITION SALTS THEREOF. THE COMPOUNDS POSSESS ADRENERGIC B BLOCKER AND ANTIARRYTHMIC PROPERTIES.

United States Patent 3,751,429 4-(3-AM1N0-2-SUBSTIT UTED PROPOXY) INDOLE DERIVATIVES Fritz Seemann, Basel, and Franz Troxler, Bottmingen, Switzerland, assignors to Sandoz Ltd. (also known as Sandoz AG), Basel, Switzerland N0 Drawing. Continuation-impart of abandoned application Ser. No. 124,976, Mar. 16, 1971. This application Sept. 24, 1971, Ser. No. 183,631

Claims priority, application Switzerland, Mar. 24, 1970,

4,379/70; Sept. 30, 1970, 14,467/70 Int. Cl. C0711 27/56 US. Cl. 260-32614 R 18 Claims ABSTRACT OF THE DISCLOSURE This invention concerns novel compounds of the formula:

wherein R is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenylalkyl of 8 to 12 carbon atoms wherein the phenyl radical is separated from the nitrogen atom by at least 2 carbon atoms, 1,1-dimethyl- 2-propinyl or allyl, R is hydrogen, methyl, carbamoyl, or carbamoyl mono or disubstituted by alkyl of 1 to 4 carbon atoms, R is hydrogen or methyl, and R, is alkyl of 1 to 17 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms substituted by one or more alkyl substituents of 1 to 4 carbon atoms, phenyl, phenyl monosubstituted by methyl, methoxy, fluorine or chlorine, or chloroalkyl of 1 to 7 carbon atoms, and acid addition salts thereof.

The compounds possess adrenergic B blocker and antiarrythmic properties.

This application is a continuation-in-part of copending application Ser. No. 124,976, filed Mar. 16, 1971, and now abandoned.

This invention relates to heterocyclic compounds.

The present invention provides compounds of Formula I,

wherein R is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenylalkyl of 8 to 12 carbon atoms wherein the phenyl radical is separated from the nitrogen atom by at least 2 carbon atoms, 1,1-dimethyl-2- propinyl or allyl,

R is hydrogen, methyl, carbamoyl, or carbamoyl monoor disubstituted by alkyl of 1 to 4 carbon atoms,

R is hydrogen or methyl, and

R is alkyl of 1 to 17 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms substituted by one or more alkyl substituents of 1 to 4 carbon atoms, phenyl, phenyl monosubstituted by methyl, methoxy, fluorine or chlorine, or chloroalkyl of 1 to 7 carbon atoms,

'ice

and acid addition salts thereof.

When R is alkyl, this is preferably branched, especially on the a carbon atom. Favourable results are obtained, for example, with isopropyl, sechutyl, tert.butyl, tort.- pentyl or 3-pentyl.

When R is phenylalkyl, this contains up to 12 carbon atoms and examples are 3-phenylpropyl, 1,1-dimethyl-3- phenylpropyl and 1-methyl-2-phenylethyl.

When R is cycloalkyl substituted by alkyl, the preferred alkyl is methyl, as for example in l-methylcyclohexyl.

When R, is a mono-substituted phenyl radical, this may be p-tolyl, o-chlorophenyl, m-methoxyphenyl or p-fluorophenyl.

When R is chloroalkyl, this contains 1 to 7 carbon atoms and examples of suitable chloroalkyl groups are chloromethyl and 3-chloropropyl.

Further, in accordance with the invention a compound of Formula I may be obtained by a process comprising:

(a) Acylating a compound of Formula H,

N R: H with an acylating agent of Formula X,

R,COOH (X) wherein R R and R of Formula H and R, of Formula X are as defined above,

wherein R R R and R are as defined above.

The term reactive acid functional derivative includes the acid anhydride and the acid halide.

The compounds of Formula I may exist in free base or acid addition salt forms and conversion of the free base to the acid addition salt form or vice-versa may be efiected in conventional manner.

The production of a compound of Formula I may, for example, be eifected as follows:

In accordance with process (a) an excess of an acid of Formula X is added to a compound of Formula II, and an excess of the corresponding anhydride is added to the resulting reaction mixture.

If desired, the reaction may be eifected in an inert solvent, e.g. hexametapol, a chlorinated aliphatic hydrocarbon such as chloroform, or a cyclic or open-chain ether such as dioxane.

The reaction temperature may range between room temperature and approximately 100 C. The reaction period is dependent on the reaction temperature.

After stirring for several hours the reaction mixture may be worked up by pouring it on ice, rendering it alkaline with an alkali or ammonia, and extracting with an inert, water-immiscible organic solvent, e.g. ethyl acetate, a cyclic or open-chain ether such as diethyl ether, or a chlorinated aliphatic hydrocarbon such as methylene chloride.

The working up stage should naturally be elfected carefully, since otherwise the ester group is again split.

The addition of the acid of Formula X may be omitted when the compound of Formula H is used in the form of an acid addition salt with a suitable mineral acid, e.g. hydrochloric acid. The danger of an N-acylation is excluuded by the protonization of the amino group of the aminopropoxy side chain; however, protonization is not always necessary, especially when R is joined with a tert.carbon atom on the nitrogen atom. When the reaction is efiected in the presence of, e.g. hydrogen chloride, the compound of Formula I crystallizes in the form of a hydrochloride and working up of the reaction mixture can be omitted.

Acylation may naturally likewise be effected with an acid halide. In this case the reaction is preferably effected at room temperature or at a slightly elevated temperature.

The debenzylation in accordance with process (b) may, for example, be effected by hydrogenation in the presence of a catalyst, preferably a palladium catalyst, in an inert organic solvent, e.g. ethyl acetate, glacial acetic acid, or a cyclic or open-chain ether such as diethyl ether, and is preferably effected at room temperature and normal pressure. After hydrogenation is complete the catalyst is filtered oh? and the filtrate is evaporated to dryness.

The compounds of Formulae II and III are new.

The compounds of Formula II may, for example, be obtained by reacting a compound of Formula IV,

N H (IV) wherein R and R are as defined above,

with an epihalohydrin, preferably epichlorhydrin or epibromhydrin, and condensing the resulting reaction product with an amine of Formula V,

H NR

wherein R is as defined above.

The production of compounds of Formula III may be effected by acylating a compound of Formula VI,

wherein R R and R of Formula VI and R of Formula Xa are as defined above.

or a reactive acid functional derivative thereof, e.g., in a manner analogous to the process described in The compound of Formula VI may be produced in a manner analogous to that described for the compounds of Formula II, using a compound of Formula IV, and a compound of Formula VII,

I N [CONRR H (IVa) wherein R is as defined above, and R and R are hydrogen or lower alkyl,

may be obtained by catalytic debenzylation of a compound of Formula VIII,

(f-Benzyl I N ICONRR wherein R, R' and R are as defined above.

The compounds of Formula VIII are also new.

4-benzyloxyindole-2-carboxylic acid amides may be obtained by reacting 4-benzyloxyindole-Z-carboxylic acid chloride with a corresponding monoor disubstituted amine or with ammonia.

4 benzyloxy-3-methylindole-2-carboxylic acid amides may, for example, be obtained from a 4-benzyloxyindole- 2-carboxylic acid ester by aminomethylation under the conditions of a Mannich reaction, quaternization of the resulting Mannich base and subsequent reduction with sodium borohydride to the corresponding Z-benzyloxy-S- methylindole-Z-carboxylic acid ester, saponification of the resulting ester, conversion of the resulting 4-benzyloxy-3- methylindole-Z-carboxylic acid into its acid chloride and subsequent reaction of this with a monoor disubstituted amine or with ammonia.

Insofar as the production of the starting materials is not particularly described, these are known or may be produced in accordance with known processes or in a manner analogous to the processes described herein or to known processes.

The compounds of Formula I may be produced and isolated in free base form or in the form of acid addition salts.

With inorganic acids, e.g. hydrogen chloride, hydrogen bromide or sulphuric acid, or with organic acids such as oxalic, fumaric, maleic, tartaric, benzoic, methane-, ethaneor p-toluenesulphonic acid or N-cyclohexylsulphamic acid, the free base forms may be converted to acid addition salt forms which are usually water-soluble. The acid addition salt forms may be converted into the free base forms or vice versa in manner known per se.

The compounds of Formula I and pharmaceutically acceptable acid addition salts thereof are useful because they possess pharmacological activity in animals. More particularly, the compounds are useful in the treatment of angina pectoris and heart rhythm disorders including tachycardia. This is indicated by a blocking effect on the adrenergic fl-receptors, as shown by an inhibition in vitro of the positive inotropic adrenalin effect and an inhibi- (VIII) tion of the tachycardia and hypotension caused by isoproterenol [1 (3,4-dihydroxyphenyl)-2-isopropylaminoethanol] in the narcotized animal (cat).

For the above mentioned use, the dosage administered will naturally vary depending on the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained at daily dosages between about 0.1 and 7 mg./kg. animal body Weight, conveniently given in divided doses 2 to 3 times a day or in sustained release form. For larger mammals, the daily dosage is between about and 500 mg. and unit dosage forms suitable for oral administration contain between about 3 and 250 mg. of the compound, in association with a pharmaceutical carrier or diluent.

The compounds may he prepared in the form of pharmaceutical compositions containing in addition pharmaceutical carriers, e.g. lactose, starch, talc, stearic acid, Water, alcohols, natural or hardened oils and waxes, and the compositions may also contain suitable preserving, stabilizing or wetting agents, solubilizers, sweetening or colouring substances and fiavourings.

In the following non-limitative examples all temperatures are indicated in degree centigrade and are uncorrected.

EXAMPLE 1 4-(2-heptanoyloxy-3-isopropylaminopropoxy) indole [process variant (a)] A mixture of 50 g. of 4-(Z-hydroxy-3-isopropylaminopropoxyfindole, 255 cc. of enanthic acid and 50 g. of enanthic acid anhydride is stirred at room temperature until the material dissolves completely and is subsequently allowed to stand for 16 hours. The mixture is poured on approximately 500 g. of ice, approximately 300 cc. of ether are added and the mixture is rendered alkaline with a 10% aqueous ammonia solution While stirring and continuously adding a further amount of ice. The ethereal phase is separated, dried over magnesium sulphate and concentrated by evaporation at reduced pressure. The resulting oily title compound is subsequently converted into its hydrogen maleate and this is recrystallized from acetone. M.P. 109-112".

EXAMPLE 2 4-(Z-isobutyryloxy-3-isopropylaminopropoxy) indole [process variant (a)] The process is efi'ected in a manner analogous to that described in Example 1, except that isobutyric acid/isobutyric acid anhydride is used in place of enanthic acid/ enanthic acid anhydride. The hydrogen maleate of the title compound crystallizes from ethanol/ethyl acetate in prism druses having a M.P. of 123-126.

EXAMPLE 3 4-(2-cyclohexylcarbonyloxy-3-isopropylaminopropoxy)indole [process variant (a)] The process is efiected in a manner analogous to that described in Example 1, except that cyclohexanecarboxylic acid/cyclohexanecarboxylic acid anhydride is used in place of enanthic acid/enanthic acid anhydride, and in place of cyclohexanecarboxylic acid double the amount of hexamethylphosphoric acid triamide is used as solvent. The hydrogen maleate of the title compound crystallizes from ethyl acetate in druses having a M.P. of 135-138.

EXAMPLE 4 4- [2- 2,2-dimethyl) pentanoyloxy-3-isopropylaminopropoxy1indole [process variant (a)] The process is efiected in a manner analogous to that described in Example 1, except that 2,2-dimethylvaleric acid/2,2-dimethylvaleric acid anhydride is used in place of enanthic acid/enanthic acid anhydride. The hydrogen maleate of the title compound crystallizes from ethanol in prisms having a M.P. of 174-17 6.

6 EXAMPLE 5 4- [2-( 2,2-dimethylbutyryloxy -3 -isopropylaminopropoxy1indole [process variant (a)] The process is effected in a manner analogous to that described in Example 1, except that 2,2-dimethylbutyric acid/2,2-dimethylbutyric acid anhydride is used in place of enanthic acid/enanthic acid anhydride. The hydrogen oxalate of the title compound crystallizes from ethanol in druses having a M.P. of 161-163 EXAMPLE 6 4- [2- (2-ethylbutyryloxy) -3-isopropylaminopropoxy] indole [process variant (a)] The process is ellected in a manner analogous to that described in Example 1, except that Z-ethylbutyric acid/ Z-ethylbutyric acid anhydride is used in place of enanthic acid/enanthic acid anhydride. The hydrogen oxalate of the title compound crystallizes from ethanol in shapeless prisms having a M.P. of 182-185".

EXAMPLE 7 4- (Z-acetoxy- 3-isopropylaminopropoxy) indole [process variant (a)] 12.4 g. of 4-(2-hydroxy-3-isopropylaminopropoxy)indole are suspended in 50 cc. of glacial acetic acid, and after the addition of 10 cc. of acetic anhydride the mixture is stirred at room temperature for 16 hours. The mixture is poured on 250 g. of ice and is rendered alkaline with concentrated aqueous ammonia while cooling. The reaction mixture is extracted with ether, the combined ethereal extracts are dried over magnesium sulphate and concentrated by evaporation at reduced pressure. The cyclohexylsulphamate of the resulting oily title compound crystallizes from methanol/ ether in fine needles having a M.P. of 158-159.

EXAMPLE 8 4-(2-benzoyloxy-3-isopropylaminopropoxy)indole [process variant (a)] A suspension of 7.14 g. of benzoic acid anhydride in 50 cc. of hexametapol is added dropwise to a suspension cooled to 0 of 7.44 g. of 4-(2-hydroxy-3-isopropylaminopropoxy)indole and 66 g. of benzoic acid in cc. of hexametapol, and the mixture is stirred at 0-5" for 24 hours. The reaction mixture is subsequently poured on ice, approximately 500 cc. of ether are added and stirring is effected for 1 hour. The mixture is then rendered alkaline with a 10% ammonia solution while cooling, the ethereal phase is separated and dried over magnesium sulphate. The evaporation residue of this ethereal phase is chromatographed on silica gel with methylene chloride, and the oily title compound is finally converted into its hydrogen oxalate; long needles from ethanol/ethyl acetate. M.P. 178-181".

EXAMPLE 9 4-[2-(4-chlorobutyryloxy)-3-isopropylaminopropoxy] indole [process variant (a)] The process is efiected in a manner analogous to that described in Example 8, except that 4-chlorobutyric acid/ 4-chlorobutyric acid anhydride is used in place of benzoic acid/benzoic acid anhydride. The hydrogen oxalate of the title compound crystallizes from ethanol/benzene. M.P. 159-161".

EXAMPLE 10 4- 3 (2-methyl-3 -butin-2-ylamino )-2-pivaloyloxypropoxy]indole [process variant (a)] The process is efiected in a manner analogous to that described in Example 8, except that pivalic acid/pivalic acid anhydride is used in place of benzoic acid/benzoic acid anhydride. The hydrogen oxalate of the title compound crystallizes from ethanol/benzene. M.P. 192-194".

7 EXAMPLE 11 4- 3 -isopropylamino-2-( 1-methylcyclohexylcarbonyloxy)propoxy]indole [process variant (a)] The process is effected in a manner analogous to that described in Example 8, except that l-methyl-l-cyclohexanecarboxylic acid/ l-methyl-l-cyclohexanecarboxylic acid anhydride is used in place of benzoic acid anhydride. The hydrogen oxalate of the title compound has a M.P. of 160-164 from ethanol/ethyl acetate.

EXAMPLE 12 2-carbamoyl-4- (3 -isopropylamino-Z-pivaloyloxypropoxy)indole [process variant (a)] 4.5 g. of Z-carbamoyl -4-(2-hydroxy-3-isopropylaminopropoxy)indole are stirred at room temperature for 14 hours together with 2.98 g. of pivalic acid anhydride and 28.5 g. of pivalic acid. The reaction mixture is subsequently poured on ice, is stirred for 1 hour in order to decompose the excess anhydride and is then rendered alkaline with a 10% ammonia solution in the presence of 300 cc. of ether while cooling with ice. The ethereal phase is dried over magnesium sulphate, is concentrated by evaporation at reduced pressure and the crystalline residue is recyrstallized from ethyl acetate. The title compound has a M.P. of 177-180".

The 2-carbamoyl-4-(2 hydroxy-3-isopropylaminopropoxy)indole, required as starting material, is obtained by reacting 4-(2-hydroxy-3-isopropylaminopropoxy)indole-2- carboxylic acid ethyl ester (M.P. 149151) with ammonia. M.P. 155-158 after recrystallization from ethyl acetate/ethanol.

EXAMPLE 13 4- (2-heptanoyloxy-3-isopropylaminopropoxy indole [process variant (b)] 8 g. of 4-(3-benzylisopropylamino-2-heptanoyloxypropoxy)indole are taken up in 250 cc. of tetrahydrofuran and debenzylation is effected with hydrogen in the presence of g. of a palladium catalyst (5% of Pd on charcoal) to obtain the title compound. The hydrogen maleate has a M.P. of 109-112 after crystallization from acetone.

The 4-(3-benzylisopropylamino 2 heptanoyloxypropoxy)indole, required as starting material, may be produced as follows:

10.6 g. of enanthic acid anhydride are added to a solution of 12 g. of 4-(3-benzylisopropylamino-2-hydroxypropoxy)indole in 150 cc. of dioxane while stirring, and stirring is continued for a further 3 hours at room temperature. The reaction mixture is subsequently poured on ice, approximately 300 cc. of ether are added and the mixture is rendered alkaline with a 2 N ammonia solution while stirring and cooling. The ethereal phase is separated, dried over magnesium sulphate and concentrated by evaporation. The oily residue is chromatographed on 500 g. of silica gel with methylene chloride, whereby pure 4-(3- benzylisopropylamino 2 heptanoyloxypropoxy)indole is obtained as an oil.

EXAMPLE 14 4- (2-isobutyryloxy-3 -isopropylaminopropoxy indole [process variant (b)] The process is elfected in a manner analogous to that described in Example 13, and the title compound is obtained by debenzylation of 4-(3-benzylisopropylamino-2- isobutyryloxypropoxy)indole. The hydrogen maleate of the title compound crystallizes from ethanol/ ethyl acetate in prism druses having a M.P. of 123-126.

The 4-(3-benzylisopropylamino 2 isobutyryloxypropoxy)indole, required as starting material, is obtained as described in Example 13 for the production of 4-(3-benzylisopropylamino-2-heptanoyloxypr0poxy)indole, except that isobutyric acid anhydride is used in place of enanthic acid anhydride.

EXAMPLE 15 4- 2-cyclohexylcarbonyloxy-3-is opropylaminoproproxy)indole [process variant (b)] EX'AMPLB 16 4- [2- 2,2-dimethylpentanoyloxy) -3-isopropylaminopropoxy]indole [process variant (b)] The process is effected in a manner analogous to that described in Example 13, and the title compound is obtained by debenzylation of 4-[3-benzylisopropylamino-2- (2,2-dimethylpentanoyloxy)propoxy]indole. The hydrogen oxalate of the title compound crystallizes from ethanol in prisms having a M.P. of 174176.

The 4 [3 benzylisopropylamino-Z-(2,2-dimethylpentanoy1oxy)propoxy]indole, required as starting material, is obtained as described in Example 13 for the production of 4 (3 benzylisopropylamino-2-heptanoyloxypropoxy) indole, except that 2,2-dimethylvaleric acid anhydride is used in place of enanthic acid anhydride.

EXAMPLE 17 4-[2-(2,2-dimethylbutyryloxy)-3-isopropylaminopropoxy]indole [process variant (b)] The process is efiected in a manner analogous to that described in Example 13, and the title compound is obtained by debenzylation of 4-[3-benzylisopropylamino- 2-(2,2-dimethylbutyryloxy)propoxy]indole. The hydrogen oxalate of the title compound crystallizes from ethanol in druses having a M.P. of 161-163".

The 4 [3 benzylisopropylamino-Z-(2,2-dimethy1butyryloxy)propoxy]indole, required as starting material, is obtained as described in Example 13 for the production of 4-( 3 benzylisopropylamino-2-heptanoyloxypropoxy) indole, except that 2,2-dimethylbutyric acid anhydride is used in place of enanthic acid anhydride.

EXAMPLE 18 4- [2- 2-ethylbutyryloxy) -3 -isopropylaminopropoxy]indole [process variant (b)] The process is elfected in a manner analogous to that described in Example 13, and the title compound is obtained by debenzylation of 4-[3-benzylisopropylamino- 2 (ethylbutyryloxy)propoxy]indole. The hydrogen oxalate of the title compound crystallizes from ethanol in shapeless prisms having a M.P. of 182-185 The 4[3-benzylisopropylamino-2 (Z-ethylbutyryloxy) propoxy]indole, required as starting material, is obtained as described in Example 13 for the production of 4-(3- benzylisopropylamino 2. heptanoyloxypropoxy)indole, except that 2-ethylbutyric acid anhydride is used in place of enanthic acid anhydride.

EXAMPLE 19 4-(2-acetoxy-3-isopropylaminopropoxy)indole [process variant (b)] 3.9 g. of 4-(2-acetoxy-3-benzylisopropylaminopropoxy) indole are taken up in 300 cc. of ethyl acetate, and the mixture is shaken with hydrogen in the presence of a palladium catalyst (5% of Pd on charcoal) until the taking up of hydrogen stops. After removing the catalyst the title compound is converted into its cyclohexylsulphamate having a M.P. of 158-159.

The 4-(Z-acetoxy-3-isopropylaminopropoxy)indole, required as starting material, may be obtained as follows:

29.3 g. of 4-(3-benzylisopropylamino-Z-hydroxypropoxy)indole, 66 g. of anhydrous sodium acetate and 130 cc. of acetic anhydride are heated to the boil for hours. The mixture is then poured on approximately 500 g. of ice and is rendered alkaline with concentrated aqueous ammonia while cooling. The reaction mixture is extracted with ethyl acetate, the combined extracts are dried over magnesium sulphate and concentrated by evaporation at reduced pressure.

EXAMPLE 20 4- [3-isopropylamino-2-( l-methylcyclohexylcarbonyloxy)propoxy]indole [process variant (b)] 5.3 g .of 4-[3-benzylisopropylamino-2-(l-methylcyclohexylcarbonyloxy)propoxy1indole are dissolved in 250 cc. of glacial acetic acid, and the solution is shaken with hydrogen in the presence of a palladium catalyst (5% of Pd on charcoal) until the taking up of hydrogen stops. The catalyst is filtered oil, the glacial acetic acid is evaporated at reduced pressure and the residue is extracted between ether and water. The combined aqueous phases are rendered weakly alkaline at 0 with a saturated sodium bicarbonate solution and extraction is effected with methylene chloride. The methylene chloride phases which have been dried over magnesium sulphate are then directly added to a solution of 1.15 g. of oxalic acid in approximately 50 cc. of ethanol, the solution is somewhat concentrated and ethyl acetate is added until crystallization commences. The hydrogen oxalate of the title compound has a M.P. of 160-164".

The benzylisopropylamino compound required as starting material is obtained by reacting 4-(3-benzylisoprop'ylamino-Z-hydroxypropoxy)indole in dioxane with l-methyl-l-cyclohexanecarboxylic acid chloride in the presence of pyridine or triethylamine. The compound is oily.

EXAMPLE 21 4-(2-benzoyloxy-3-isopropylaminopropoxy)indole [process variant (b)] The process is effected in a manner analogous to that described in Example 20, and the title compound is obtained by debenzylation of 4-(2-benzoyloxy-3-benzylisopropylaminopropoxy)indole. The hydrogen oxalate of the title compound crystalizes from ethanol/ethyl acetate in long needles having a M.P. of 178-181".

The 4-(2-benzoyloxy-3-benzylisopropylaminopropoxy) indole, required as starting material, is obtained as described in Example 20 for the product of 4-[3-benzy1isopropylamino 2 (1 methylcyclohexylcarbonyloxy)propoxy]indole, except that benzoyl chloride is used in place of l-methyl-l-cyclohexanecarboxylic acid chloride.

EXAMPLE 22 4-[2- (4-chlorobutyryloxy) )-3-isopropylaminopropoxy1indole [process variant (b)] The process is effected in a manner analogous to that described in Example 20, and the title compound is obtained by debenzylation of 4-[Ii-benzylisopropylamino- 2-(4-chlorobutyrylox'y)propoxylindole. The hydrogen oxalate of the title compound crystallizes from ethanol/ benzene. M.P. 159-161".

The 4-[3-benzylisopropylamino-2-(4-chlorobutyryloxy) propoxy]indole, required as starting material, is obtained as described in Example 20 for the production of 4-[3- benzylisopropylamino 2 (l-methylcyclohexylcarbonyloxy)propoxy]indole, except that 4-chlorobutyr'yl chloride is used in place of l-methyl-lcyclohexanecarboxylic acid chloride.

10 EXAMPLE 23 2-carbamoyl-4-(3-isopropylamino-Z-pivaloyloxypropoxy)indole [process variant (b)] 3.2 g. of 4-(3-benzylisopropylamino-2-pivaloyloxypropoxyJ-Z-car-bamoylindole are taken up in 1000 cc. of dioxane, and the mixture is debenzylated with hydrogen in the presence of 1.5 g. of a palladium catalyst (5% of Pd on charcoal) to obtain the title compound. M.P. 177-180 from ethyl acetate.

The starting material is produced by production of 2-carbamoyl-4-benzyloxyindole (M.P. 187-189") from 4-ben2.yloxyindole-2-carboxylic acid via the acid chloride and production of 2-carbamoyl-4-hydroxyindole by debenzylation of 2-carbamoyll-benzyloxyindole. Z-carbamoyl-4-hydroxyindole is reacted with epichlorhydrin in the presence of a few drops of piperidine to obtain Z-carbamoyl-4-(2,3-epoxypropoxy)indole, and the latter com pound is reacted in boiling dioxane with benzylisopropylamine to obtain 4-(3-benzylisopropylamino-Z-hydroxypropoxy)-2-carbamoylindole.

5,6 g. of 4-(3-benzylisopropylamino 2 hydroxypropoxy)-2-carbamoylindole are dissolved in 77 cc. of dioxane, 3.0 g. of pivalic acid anhydride are added and the mixture is stirred at room temperature for 5 hours. The mixture is subsequently poured into 500 cc. of Water and is rendered alkaline with a 2 N ammonia solution while cooling. The aqueous phase is extracted with ether, the ethereal extracts are dried over magnesium sulphate and concentrated by evaporation. The oily residue is chromatographed on 280 g. of silica gel with methylene chloride, whereby pure, oily 4-(3-benzylisopropylamino-2- pivaloyloxypropyloxy)-2-carbamoylindole is obtained.

EXAMPLE 24 4- 3 -isopropylamino2-pivaloyloxypro p oxy) indole 12.4 g. of 4-(Z-hydroxy-3-isopropylaminopropoxy)indole are suspended in cc. of pivalic acid, and after the addition of 10 cc. of pivalic acid anhydride, the mixture is stirred at room temperature for 16 hours. The reaction mixture is poured on 250 g. of ice and is made alkaline with concentrated aqueous ammonia while cooling. The reaction mixture is extracted with ether, the combined ether extracts are dried over magnesium sulphate and concentrated by evaporation at reduced pressure.

The hydrogen maleate of the heading compound crystallizes from acetone in white crystals having a M.P. oi 123-126".

EXAMPLE 25 4- (3-isopropylamino-2-pivaloy1oxypropoxy) Z-methylindole A mixture of 50 g. of 4-(2-hydroxy-3-isopropylaminopropoxy)-2-methylindole, 350 cc. of pivalic acid and 37.2 g. of pivalic acid anhydride is stirred at room temperature until the material dissolves completely and is subsequently allowed to stand for 16 hours. The reaction mixture is poured on about 500 g. of ice, about 300 cc. of ether are added, and the mixture is subsequently made alkaline with a 10% aqueous ammonia solution while stirring and continuously adding a further quantity of ice. The ethereal phase is separated, dried over magnesium sulphate and concentrated by evaporation at reduced pressure. The resulting oily title compound is subsequently converted into its hydrogen malonate and this is recrystallized from ethanol/ethyl acetate; druses, having a M.P. of 132-134.

EXAMPLE 26 4-(3-tert.butylamine-Z-pivaloyloxypropoxy)indole 2 g. of 4-(3-tert.butylamino-Z-hydroxypropoxy)indole are dissolved in 13.5 g. of pivalic acid, and after the addition of 1.5 g. of pivalic acid anhydride, the reaction mixture is stirred at room temperature for 30 hours.

The mixture is poured on ice, made alkaline with concentrated aqueous ammonia and extraction is elfected with ether. The combined ethereal extracts are dried over magnesium sulphate and concentrated by evaporation at reduced pressure.

The hydrogen maleate of the title compound crystallizes from ethanol/ethyl acetate in druses having a M.P. of 155-157.

The 4-(3-tert.butylamino-Z-hydroxypropoxy)indole, required as starting material, is obtained by reacting 4-hydroxy-indole with epichlorhydrin to obtain 4-(2-epoxypropoxy)indole (M.P. 65-67, from benzene) and reacting this with tert.butyl amine in dioxane to obtain 4-(3-tert.butylamnio-2 hydroxypropoxy)indole (M.P. 170-171, from ethanol).

EXAMPLE 27 4- 3- (3-phenylpropylamino) -2-pivaloxypropoxy] indole This compound is obtained in a manner analogous to that described in Example 26, except that the corresponding 4-[2-hydroxy-3-(3 phenylpropylamino)propoxy]indole is used in place of 4-(3-tert.-butylamino-2-hydroxypropoxy)indole.

The oxalate of the title compound crystallizes from ethanol/ethyl acetate and has a M.P. of 183-185".

EXAMPLE 28 4- (3-isopropylamino-2-pivaloyloxypropoxy indole '5 g. of 4-(3-benzylisopropylamino-Z-pivaloyloxypropoxy)indole are shaken in 100 cc. of glacial acetic acid and in the presence of 1 g. of a palladium catalyst (5% of palladium on charcoal) with hydrogen, until the taking up of hydrogen is complete. The catalyst is filtered 0E and the glacial acetic acid is evaporated at reduced pressure. The residue is dissolved in water and the solution is made alkaline with concentrated aqueous ammonia while cooling with ice. Extraction is effected with ether, the extracts are dried over magnesium sulphate and concentrated by evaporation at reduced pressure.

The hydrogen maleate of the title compound crystallizes from acetone and has a M.P. of 123-126.

The 4-(3-benzylisopropylamino-2-pivaloyloxypropoxy) indole, required as starting material, is obtained as a viscous resin by reacting 4-(3-benzylisopropylamino-2- hydroxypropoxy)indole with pivalic acid anhydride in a manner analogous to that described in Example 24, or in dioxane as solvent.

The following compounds are produced in a manner analogous to that described in Example 28:

4-(3-isopropylamino-2-pivaloyloxypropoxy)-2-methy1- indole hydrogen malonate having a M.P. of 132-134",

4-(3-tert.butylamino 2 pivaloyloxypropoxy)indole hydrogen maleate having a M.P. of 155-157",

4-[3-(3 phenylpropylamino) 2-pivaloyloxypropoxy] indole oxalate having a M.P. of l83l85.

The following compounds may likewise be obtained in accordance with the process variants (a) and (b) of the invention:

4- (2-heptanoyloxy-3 -isoproplyaminopropoxy) -2-methylindole,

4- 3-tert.butylamino-2-heptanoyloxypropoxy) indole,

4- [2-heptanoyloxy-3- 3-pentylarnino propoxy] indole,

4- 2-isobutyryloxy-3-isopropylaminoprop oxy) -2- methylindole,

4- (2-acetoxy-3-isopropylaminoprop oxy) -2-methylindole,

4- 2-acetoxy-3-isopropylaminopropoxy) -2,3-dimethylindole,

4- 2- (2,2-dimethylpentanoyloxy) -3- 3-pentylamino) propoxy] indole,

4- [3-tert.butylamino-2- (2,2-dimethylpentanoyloxy) propoxy]indole,

4- [2- 2-ethylbutyryloxy -3-tert.butylaminopropoxy] indole,

4- [2- 2, Z-dimethylbutyryloxy) -3- (3 -pentylamino) propoxy] indole,

4- 3-cyclopropy1amino-2- (2,2-dimethylbutyryloxy) propoxy] indole,

4- 3-sec.butylamino-2- (2,2-dimethylbutyryloxy) propoxy] indole,

4- [2-capr-inoy1oxy-3 1,1-dimethyl-3 -phenylpropylamino propoxy] indole,

4- (2-caprinoyloxy-3-tert.p entylaminopropoxy) indole,

4- (Z-caprinoyloxy-3-isopropylaminoprop oxy indole,

4- 3-isopropylarnino-2-stearoyloxyprop oxy indole,

4- (3-cyclohexylamino-Z-pivaloyloxyprop oxy) -2-methylindole,

2-carba'rnoyl 4- [3- (3-pentylam-ino -2-pivaloyloxypropoxy] indole,

2-dimethylcarbamoyl-4- (3 -isopropylamino-2-pivaloyloxypropoxy indole,

4- (3 -isopropylamino-Z-pivaloyloxypropoxy) -2-methylcarb amoylindole,

4- 3-isopropylamino-2-pivaloyloxyprop oxy) -2-isopropyl-carbarnoylindole,

4- (3-tert.butylamino-2-pivaloyloxypropoxy) -3-methyl- 2-dimethylcarbamoylindole,

Z-carbamoyll 3-tert.pentylamino-Z-pivaloyloxypropoxy indole,

2-carbamoyl-4- 3-cyclopropylamino-2-pivaloyloxypropoxy) indole,

2-carbamoyl-4- 3-( 1-methyl-3-phenylpropylarnino) -2- pivaolyloxypropoxyl] indole,

2-carbamyl-4- (2-heptanoyloxy-3-isopropylaminopropoxy) indole,

2-carbamoyl-4- [2- 2,2-dimethylpentanoyloxy -3-isopropylaminopropoxyl] indole,

4- [2- 4-chlorobutyryloxy -3-tert.pentylaminopropoxy] indole,

4- 3-sec.butylamino-2- (4-chlorobutyryloxy propoxy] indole,

4-( 2-chl0roacetoxy-3-isopropylaminopropoxy -2 methyl-indole,

4- [2-chloroacetoxy-3-( 1-methyl-Z-phenylethylamino) propoxy] indole,

4- [2- Z-chloro-Z-propionyloxy) -3 -cyclopropylaminoproxy] -2-carb amylindole,

4- 2;jc3iclohexylc arbonyloxy-3 3 -pentylamino prop oxy] 4- 3-tert.butylamino-2-( 1-methylcyclohexylcarbonyloxy) propoxy] indole,

4- 2-cyclopentylcarbonyloxy-3-isopropylaminopropoxy) indole,

2-carb amoyl-4- [2-acycloheptylcarb onyloxy-3 3 -phenylpropylamino propoxy] indole,

4- [2-benzoyloxy-3- 3-pentylamino) propoxy] indole,

4- 2-benzoyloxy-3-isopropylaminopropoxy) -2-methylindole,

4- [2- (2-chlorobenzoyloxy) -3-tert.pentylaminopropoxy] 2,3-dimethylindole,

2-carbamoyl-4- [3 -tert.butylamino-2- 4-fluorob enzoyloxy) propoxy] indole,

4- [2-(3-methoxybenzoyloxy) -3-isopropylaminopropoxy] Z-methylindole,

2-butylcarbamoyl-4- [2- 4-methylbenzoyloxy) -3-cyclop-ropylaminoprop oxy] indole.

The following compounds may moreover be obtained in accordance with the process variant (a) of the invention:

4- 3- 2-methyl-3-butin-2-ylamino) 2-stearoyloxypropoxy]indole,

4-[2-heptanoyloxy-3-(Z-methyl-3-butin-2-ylamino) propoxyindole,

4- [2-isobutyryloxy-3- Z-methyl-3-butin-2-ylamino) propoxy]2-methylindole,

What is claimed is: 1. A compound of the formula:

wherein R is alkyl of l to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenylalkyl of 8 to 12 carbon atoms wherein the phenyl radical is separated from the nitrogen atom by at least Z-carbon atoms, 1,1-dimethyl-2- propinyl or allyl,

R is hydrogen, methyl, carbamoyl, or carbamoyl monoor disubstituted by alkyl of 1 to 4 carbon atoms,

R is hydrogen or methyl, and

R is alkyl of 1 to 17 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkyl of 3 to 7 carbon atoms substituted by one or more alkyl substituents of 1 to 4 carbon atoms, phenyl, phenyl monosubstituted by methyl, methoxy, fluorine or chlorine, or chloroalkyl of 1 to 7 carbon atoms,

or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1 which is 4-(2-heptanoyloxy-3-isopropylaminopropoxy)indole, or a. pharmaceutically acceptable acid addition salt thereof.

3. The compound of claim 1 which is 4-(2-isobutyryloxy-3-isopropylaminopropoxy)indole, or a pharmaceutically acceptable acid addition salt thereof.

4. The compound of claim 1 which is 4-(2-cyclohexylcarbonyloxy-3-isopropylaminopropoxy)indole, or a pharmaceutically acceptable acid addition salt thereof.

5. The compound of claim 1 which is 4-[2-(2,2-dimethyl)pentanoyloXy-3-isopropylaminopropoxy]indole, or a pharmaceutically acceptable acid addition salt thereof.

6. The compound of claim 1 which is 4- [2-(2,2-dimethylbutyryloxy) 3 isopropylaminopropoxy]indole, or a pharmaceutically acceptable acid addition salt thereof.

7. The compound of calm 1 which is 4[2-(2-ethylbutyryloxy)-3-isopropylaminopropoxy]indole, or a pharmaceutically acceptable acid addition salt thereof.

8. The compound of claim 1 which is 4-(2-acetoXy-3- isopropylaminopropoxy)indole, or a pharmaceutically acceptable acid addition salt thereof.

9. The compound of claim 1 which is 4-(2-benzyloxy- 3-isopropylaminopropoxy)indole, or a pharmaceutically acceptable acid addition salt thereof.

10. The compound of claim 1 which is 4-[2- (t-chlorobutyryloxy)-3-isopropylaminopropoxy]indole, or a pharmaceutically acceptable acid addition salt thereof.

11. The compound of claim 1 which is 4-[3-(2-methyl- 3-butin-2-ylamino) 2 pivaloyloxypropoxy]indole, or a pharmaceutically acceptable acid addition salt thereof.

12. The compound of claim 1 which is 4-[3-isopropylamino 2 (1 methylcyclohexylcarbonyloxy) propoxy] indole, or a pharmaceutically acceptable acid addition salt thereof.

13. The compound of claim 1 which is 2-carbamoyl-4- (3-isopropylamino 2 pivaloyloxypropoxy)indole, or a pharmaceutically acceptable acid addition salt thereof.

14. A compound of the formula:

wherein R; is lower alkyl, cycloalkyl of 3 or 4 carbon atoms or B-phenylpropyl, and each of R and R is is hydrogen or methyl,

or a pharmaceutically acceptable acid addition salt thereof.

15. The compound of claim 14 which is 4-(3-isopropylamino 2. pivaloyloxypropoxy)indole, or a pharmaceutically acceptable acid addition salt thereof.

16. The compound of claim 14 which is 4-(3-isopropylamino-2-pivaloyloxypropoxy)-2methylindole, or a pharmaceutically acceptable acid addition salt thereof.

17. The compound of claim 14 which is 4-(3-tert.butylamino 2 pivaloyloxypropoxy)indole, or a pharmaceutically acceptable acid addition salt thereof.

18. The compound of claim 14 which is 4-[3-(3-phenyl propylamino)-2-pivaloyloxypropoxy]indole, or a pharmaceutically acceptable acid addition salt thereof.

References Cited UNITED STATES PATENTS 3,471,515 10/1969 Troxler et al 260-326.1S

JOSEPH A. NARCAVAGB, Primary Examiner US. Cl. X.R. 

